Epilepsy Research (2007) 75, 75—83

journal homepage: www.elsevier.com/locate/epilepsyres

CLINICAL RESEARCH

Efficacy and safety of adjunctive zonisamide

therapy for refractory partial seizures
Michel Baulac a,∗, Ilo E. Leppik b

a
Department of Neurology, University of Paris 6, Bat. Paul Castaigne Hopital de la Pitie-Salpetrierre,
47 Boulevard de l’Hopital, 75013 Paris, France
b
University of Minnesota and MINCEP Epilepsy Care, Minneapolis, MN, USA

Received 7 November 2006; received in revised form 21 March 2007; accepted 23 April 2007
Available online 5 June 2007

KEYWORDS Summary An approach to the selection of appropriate antiepileptic drugs (AEDs) for inclu-
sion in polytherapy is to take into account both the efficacy of a drug and also its mechanism
Zonisamide;
of action and pharmacokinetic profile. The AED zonisamide is licensed in Europe and the USA
Partial seizures;
for use as adjunctive therapy in adult patients with partial onset epilepsy. Four pivotal clinical
Adjunctive therapy;
studies in patients with refractory partial seizures demonstrated that zonisamide as an add-on
Review
was most effective at doses of ≥300 mg/day, with responder rates (≥50% reduction from base-
line in seizure frequency) ranging from 28 to 47% for all seizures. In addition, zonisamide has
a unique combination of multiple mechanisms of action that are potentially complementary
with concomitant AEDs. Zonisamide has no clinically relevant effects on the pharmacokinetics
of other commonly used AEDs, however, co-administration with cytochrome P450 3A4 (CYP3A4)
inducers or inhibitors may change zonisamide’s pharmacokinetic profile. Zonisamide is well tol-
erated with the majority of adverse events being mild-to-moderate and generally manageable.
The tolerability of zonisamide has also been shown to improve with slower drug titration and
duration of drug treatment. These characteristics suggest that zonisamide may be suitable as
a key adjunct in rational polytherapy.
© 2007 Elsevier B.V. All rights reserved.

Contents

Introduction............................................................................................................... 76
Pharmacokinetics and pharmacodynamics ................................................................................. 77
Efficacy of zonisamide..................................................................................................... 77
Placebo-controlled studies ........................................................................................... 77
Dose—response relationship .......................................................................................... 77

∗ Corresponding author. Tel.: +33 1 42 16 1811/0; fax: +33 1 44 24 52 47.

E-mail address: michel.baulac@psl.ap-hop-paris.fr (M. Baulac).

0920-1211/$ — see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2007.04.007
76 M. Baulac, I.E. Leppik

Open-label and active comparator studies............................................................................ 78

Studies in children.................................................................................................... 79
Tolerability and safety of zonisamide...................................................................................... 79
CNS-related adverse events .......................................................................................... 79
Renal calculi.......................................................................................................... 79
Weight change and appetite decrease ................................................................................ 79
Oligohydrosis in paediatric patients .................................................................................. 80
Rash .................................................................................................................. 80
Teratogenicity ........................................................................................................ 81
Conclusion ................................................................................................................ 81
Acknowledgements ...................................................................................................... 81
References .............................................................................................................. 81

Introduction of interaction with concomitant AEDs and other drugs (e.g.

Localisation-related (partial onset) epilepsy is manifested by
simple partial seizures, complex partial seizures and secon-
darily generalised seizures. More than 60% of patients with
epilepsy, including the most difficult-to-treat cases, have
partial onset epilepsy (Semah et al., 1998).
The first-line choice of antiepileptic drugs (AEDs) for
partial onset epilepsy varies geographically, and the wide
range includes carbamazepine, sodium valproate, pheny-
toin, lamotrigine and oxcarbazepine. US guidelines promote
tailoring first-line AED treatment to individual patient char-
acteristics, using the full range of available AEDs; whereas
European guidelines recommend using the older AEDs, such
as sodium valproate and carbamazepine, as first-line treat-
ments, with the newer AEDs being used only if the patient
is unresponsive or if the older AEDs are unsuitable (French
et al., 2004; Beghi, 2004; NICE, 2004). Furthermore, lam-
otrigine and oxcarbazepine are increasingly being used as
first-line choices for adults with partial seizures (Karceski
et al., 2005). However, up to 30% of patients with par-
tial seizures do not respond to AED therapy (Brodie, 2001).
Should a patient not respond to the first AED, the common
practice is to titrate upwards with a second AED while taper-
ing off the first to establish the patient on an alternative
monotherapy (NICE, 2004). Some patients not responding to
initial AED treatment have been shown to achieve freedom
from seizures by switching to an AED with an alternative
mode of action (Brodie and Mumford, 1999). Further clini-
cal observations have suggested that when two appropriate
AED monotherapy regimens have failed that there is very
limited success with the third (Kwan and Brodie, 2006).
The preferred strategy in the management of refrac-
tory epilepsy is combination therapy (Perucca and Levy,
2002). The recent introduction of several new AEDs for use
as adjuncts in refractory partial epilepsy has considerably
increased the number of potential combinations. However,
practice recommendations for when and how to combine
drugs remain empirical (Kwan and Brodie, 2006). Although
randomised controlled studies in refractory patients might
help to determine guidelines on optimal combinations of
AEDs, the size and cost involved in obtaining such data may
be prohibitive.
There are a number of considerations when select-
ing appropriate adjunctive agents for polytherapy. These
include mode of action, efficacy and tolerability profile, lack
oral contraceptives), and ease of administration.
The theoretical approach of rational polytherapy based
on mode of action suggests that patients respond favourably
to drug combinations with complementary modes of action
(Macdonald, 1996; Brodie and Mumford, 1999). There is
an absence of controlled data to inform the situation and
currently, there is no consensus as to whether any par-
ticular drug combination can improve prognosis in a given
patient/seizure type (Leppik, 2000). Therefore, a prag-
matic approach to the selection of drug combinations should
include an appraisal of each drug’s mechanism of action,
spectrum of efficacy, drug interaction potential and side
effect profile (Brodie, 2001).
Zonisamide has been available in the USA since 2000
and in Japan since 1989 and worldwide experience now
exceeds 2 million patient-years. It has been widely used
in Japan and the USA as an adjunct for refractory partial
seizures, and is now approved in Europe for this indica-
tion in adults. Zonisamide possesses a number of properties
likely to confer antiepileptic activity, including: blockade of
voltage-dependent T-type calcium channels (Suzuki et al.,
1992) and voltage-sensitive sodium channels (Schauf, 1987),
blockade of potassium-evoked glutamate response (Okada
et al., 1998), reduction of glutamate-mediated synaptic
excitation (Zhu and Rogawski, 1999) and increased GABA
release (Kawai et al., 1994). In line with these findings, clini-
cal observations suggest that zonisamide may be effective in
a diverse range of seizure types, from partial onset seizures
and their secondary generalisations to generalised epilepsy
syndromes including both primary (idiopathic) and symp-
tomatic generalised epilepsies (Seino and Fujitani, 2002).
Furthermore, zonisamide is reported to be a weak
inhibitor of carbonic anhydrase and is generally accepted
to be 100—200 times less potent in this effect than aceta-
zolamide (Masuda and Karasawa, 1993). However, this
mechanism is not believed to contribute to the antiepileptic
effects of zonisamide.
This paper reviews the efficacy and safety of zonisamide
in refractory partial seizures, based on extensive clinical
experience from registration studies and open-label evalu-
ations, relevant to the topics covered in this review. The
authors conducted a Medline literature search for all full
paper publications on zonisamide clinical trials in partial
epilepsy (no date limit applied), and a manual search of
congress abstracts for the key epilepsy congresses (includ-
Efficacy and safety of adjunctive zonisamide therapy
ing the American Academy of Neurology [AAN], American
Epilepsy Society [AES], International Epilepsy Congress [IEC]
and European Congress on Epileptology [ECE]) from 2000 to
2006. In line with its licensed indication, the review dis-
cusses zonisamide in the context of its potential as a key
adjunct for inclusion in the rational therapy of refractory
partial seizures in adults.
Pharmacokinetics and pharmacodynamics
The pharmacokinetic profile of zonisamide has shown it to
have rapid absorption, good bioavailability (not affected by
food), and a long elimination half-life (t1/2 ) of approximately
63 h in healthy volunteers. This long t1/2 permits once- or
twice-daily dosing of zonisamide in the USA (Eisai Pharma
International Ltd., 2004), although twice-daily dosing is
more commonly used for convenience of co-administration
with other AEDs. The long t1/2 also minimises the risk of
break-through seizures should the patient miss a dose. The
European licence also allows for once- or twice-daily dos-
ing following titration—–allowing flexibility in the choice of
dosing regimen (Eisai Ltd., 2006).
Zonisamide has no clinically relevant effects on the
pharmacokinetics of other commonly used AEDs (e.g. car-
bamazepine (Ragueneau-Majlessi et al., 2004), phenytoin
(Levy et al., 2004), valproate (Ragueneau-Majlessi et al.,
2005) and lamotrigine (Levy et al., 2005)). However, zon-
isamide is metabolised in part by cytochrome P450 3A4
(CYP3A4), and co-administration with CYP3A4 inducers or
inhibitors may change its pharmacokinetic profile. For exam-
ple, the t1/2 of zonisamide is reduced to 27 h when given
concomitantly with phenytoin and 36 h when given with
carbamazepine, but since the t1/2 remains above 24 h this
should not affect the zonisamide dosing interval. Indeed,
titration of zonisamide when added to a regimen contain-
ing these AEDs may be achieved more rapidly as a result of
this effect, although, conversely, care should be taken when
withdrawing the original AED. However, overall, the combi-
nation of zonisamide with phenytoin or carbamazepine is
well tolerated (Greenblatt, 1993; Levy et al., 2004).
Results from a pharmacokinetic study in 33 paediatric
patients receiving treatment with two AEDs other than
zonisamide, 16 of whom were taking AEDs with enzyme-
inducing activity (Levisohn, 2005), were consistent with
those reported in adults; concomitant administration of
enzyme inducers was associated with lower zonisamide
exposure than in non-induced paediatric patients.
Efficacy of zonisamide
Placebo-controlled studies
Four randomised, double-blind, placebo-controlled studies
involving a total of 850 patients with refractory partial
epilepsy have demonstrated significant efficacy with zon-
isamide at doses of ≥300 mg/day, compared with placebo
(Schmidt et al., 1993; Faught et al., 2001; Sackellares et
al., 2004; Brodie et al., 2005). In these studies, signifi-
cantly greater reductions from baseline were achieved in
the median number of seizures experienced per month
compared with placebo, as shown in Fig. 1 for complex
77
Figure 1 Median percentage reduction in seizure frequency
from baseline with adjunctive zonisamide or placebo from
four placebo-controlled trials (intent-to-treat [ITT] popula-
tion). * p < 0.05 vs. placebo; ** p < 0.01 vs. placebo; *** p < 0.001 vs.
placebo; **** p < 0.0001 vs. placebo. a All patients who received
at least one dose of study drug or placebo. b All patients who
received at least 7 days of treatment.
partial, all partial (i.e. simple partial and complex par-
tial) and all seizures (i.e. simple partial, complex partial
and secondarily generalised). Similarly, the responder rates
(defined as the proportion of patients achieving ≥50% reduc-
tion from baseline in seizure frequency) were greater for
patients treated with ≥300 mg/day zonisamide than for
those treated with placebo. Responder rates ranged from
30 to 45% for complex partial seizures, 27 from 44% for all
partial seizures and 28 from 47% for all seizures (Table 1).
In addition, patient and investigator global assessments of
efficacy, whilst varying between studies, were greater in
subjects receiving ≥300 mg/day zonisamide compared to
those receiving placebo (Schmidt et al., 1993; Sackellares
et al., 2004; Brodie, 2004).
In addition, seizure freedom data were analysed for
the most recent European placebo-controlled study in 351
patients with refractory partial epilepsy (Brodie et al.,
2005). In this analysis up to 9% of patients shown to remain
free of seizures for at least 28 days with the highest dose
of zonisamide (500 mg/day), despite the highly refractory
nature of this patient population (Hirsch and Duncan, 2005).
A Cochrane review of these placebo-controlled clini-
cal trials confirmed the significant efficacy of zonisamide
≥300 mg/day over placebo on responder rates (relative risk
ratio 2.44) (Chadwick and Marson, 2005). A Chi-squared test
for heterogeneity also indicated that the response to zon-
isamide was statistically consistent between the trials. The
reviewers concluded that zonisamide was effective as an
add-on treatment in patients with refractory partial onset
epilepsy.
Dose—response relationship
While zonisamide doses of ≥300 mg/day have been shown
to be the most effective, lower doses may be efficacious
in some patients. Indeed, Faught et al. (2001) reported
that zonisamide at 100 and 200 mg/day was significantly
more efficacious than placebo, both in terms of responder
78
Table 1 Responder rates for zonisamide (≥300 mg/day) from four placebo-controlled trials (intent-to-treat [ITT] population)
Study Zonisamide dose (mg/day)
Brodie et al. (2005)a 300
500
Placebo
Sackellares et al. (2004)a ≥400
Placebo
Faught et al. (2001)a 400
Placebo
Schmidt et al. (1993)b 7.0 mg/(kg day)
Placebo
a All patients who received at least one dose of study drug or placebo.
b All patients who received at least 7 days of treatment.
* p < 0.05 vs. placebo.
** p < 0.001 vs. placebo.
rates and changes in seizure frequency. This is an important
attribute for inclusion in rational polypharmacy, whereby
the dose of each treatment is individualised during titra-
tion at the initiation of therapy, and will vary between
patients depending on other AEDs already received, and also
on intrinsic factors affecting individual drug sensitivity.
In the recent pivotal study, analysis of effects with
100, 300, 500 mg/day zonisamide showed that seizure
frequency decreased and responder rate increased in a dose-
dependent manner (Brodie et al., 2005). In this study the
highest dose of zonisamide (500 mg/day) was significantly
superior to placebo in reducing all seizures, complex par-
tial seizures and all partial seizures. The 300 mg/day dose
also produced significantly greater reductions in all seizure
frequency and all partial seizures (Fig. 2).
Open-label and active comparator studies
Although randomised controlled trials provide the most
robust evidence to demonstrate efficacy, they are rarely
Figure 2 Proportions of patients experiencing a ≥ 50%
reduction in seizure frequency (responders) with adjunctive
zonisamide or placebo (primary efficacy-analysis population)
(Reproduced from Brodie et al., 2005, with permission from
Blackwell Publishing).
M. Baulac, I.E. Leppik
Responder rates per seizure type (%)
All seizures All partial seizures Complex partial
34.5 34.6 30.3
46.6** 44.3** 45.1**
17.6 20.2 22.3
28.2 26.9 30.8*
16.2 16.2 13.9
43.0* — —
22.2 — —
29.9* 30.3* 30.3*
9.4 10.9 12.7
practical or ethical for assessing response over a longer
term. Whilst uncontrolled extension studies can provide
valuable data over prolonged treatment periods, their
results should be interpreted with caution. In particular,
such studies are subject to drop out over time and a
consequential enrichment of the subjects who remain.
Therefore, where available, it is helpful to report effi-
cacy in the context of the percentage of remaining
subjects. Long-term assessment of adjunctive zonisamide
(≥300 mg/day) in partial seizures has been reported in
several such studies, evaluating treatment durations of
up to 16 years (Alapati et al., 2000; French and Ruelle,
2002; Brodie, 2004; Faught, 2004; Wroe and Brodie, 2005;
Tosches and Tisdell, 2005a,b). The results suggested that
at least for the subgroup of ‘‘responders’’ who remained
in the trials over such periods efficacy is maintained over
time. Specifically, in the extension of the main pivotal trial
(Brodie et al., 2005), treatment response (≥50% reduction
in seizure frequency) was maintained in 43, 45 and 46% of
subjects at 1, 2 and 3 years, respectively, with 65, 45 and
29% of subjects remaining in the study at these timepoints
[Wroe SJ, Personal Communication].
These response rates are in line with those reported
in earlier small-scale open-label and retrospective studies
in adults with refractory partial seizures, which reported
responder rates of 35—57% (Ono et al., 1988; Leppik et al.,
1993; Schacht et al., 2002; Saleh et al., 2003; Yagi and
Seino, 1992). However, many of these studies have not been
reported in full, making further interpretation of their find-
ings difficult.
Data using active comparators are limited. One ran-
domised, double-blind trial has compared zonisamide and
carbamazepine as an adjunctive therapy over 16 weeks
of treatment (including a dose titration phase of 4—8
weeks followed by maintenance treatment) in patients
with refractory partial seizures (Seino et al., 1988). This
study, conducted in Japan, evaluated efficacy data in
56 patients treated with zonisamide (mean maintenance
dosage 330 mg/day) and 52 patients treated with car-
bamazepine (mean maintenance dose 600 mg/day). The
frequency of partial seizures without secondary generali-
sation decreased during the study, with mean changes at
Efficacy and safety of adjunctive zonisamide therapy
Week 16 of −68.4% with zonisamide versus −46.6% with car-
bamazepine, accompanied by responder rates (defined by
≥50% reduction in total seizure frequency) of 82% for zon-
isamide and 71% for carbamazepine. These differences did
not reach statistical significance (p > 0.10). There were also
slightly more early discontinuations in the carbamazepine
group (5 versus 2 in the zonisamide group, all within the first
3 weeks, due to adverse events) but treatment groups were
comparable in all other respects (baseline characteristics,
effects of treatment on other seizure types, concomitant
medications and tolerability). However, the interpretation
of these findings, particularly the effects on other seizure
types, is limited by the small numbers of patients involved.
Studies in children
Zonisamide is currently indicated for use in adolescent (aged
12—17 years) and adult patients with partial epilepsy in the
US, and only adults in Europe. The inclusion of low numbers
of adolescents in the registration trials, and the exclusion
of children prevented determination of efficacy in these
subpopulations. Evaluation of the recent pivotal placebo-
controlled trial (Brodie et al., 2005), which included a small
number of adolescent patients (n = 39) relative to adults
(total n = 349), suggests similar proportions of responders to
zonisamide for both age groups [Eisai Ltd., Data on file(a)].
Open-label data from 14 Japanese studies in children
have been reviewed by Glauser and Pellock (2000), includ-
ing five studies of adjunctive therapy. The responder rate for
these adjunctive therapy studies was 35% of children with
partial seizures.
Another study concerned the retrospective analysis of 50
children with medically refractory epilepsies treated with
zonisamide, of whom eight had partial seizures and 42 gen-
eralised seizures. Results reported a responder rate of 44%,
although the level of response declined after 2—6 months in
10/22 responders (Henning and Eriksson, 2004). In a further
small retrospective study, three responders were reported
out of six children treated with adjunctive zonisamide ther-
apy, including one child (out of two) with partial seizures
with or without generalisation (Beitinjaneh et al., 2001).
The same caveats apply to the interpretation of these uncon-
trolled data as was discussed previously.
Tolerability and safety of zonisamide
As with all AEDs, adverse events (AEs) occurred more
frequently during treatment with zonisamide than with
placebo (Sackellares et al., 2004). Across all placebo-
controlled studies with zonisamide, AEs were reported
for 78 and 68% of zonisamide and placebo recipients,
and treatment-related AEs were reported for 61 and 49%,
respectively (Brodie, 2006). However, these AEs were
generally of mild-to-moderate severity and few AEs or
treatment-related AEs resulted in discontinuations: 20
and 19% for zonisamide groups compared with 11 and 9%
for placebo, respectively [Eisai Ltd., Data on file(b)]. In
addition, the incidence of severe AEs was no greater than
placebo in patients treated with zonisamide (Brodie et
al., 2005). Furthermore, the tolerability of zonisamide
improves with duration of drug treatment and a slower drug
79
titration reduces the incidence of AEs (Faught et al., 2004).
Table 2 summarises the AEs reported most frequently across
the four placebo-controlled adjunctive zonisamide therapy
trials [Eisai Ltd., Data on file(b)].
CNS-related adverse events
The most commonly reported treatment-related AEs with
zonisamide are of CNS origin but these are gener-
ally of mild-to-moderate severity (Brodie, 2006). Across
all placebo-controlled trials, the CNS-related AEs which
occurred more frequently with zonisamide than with
placebo were somnolence; dizziness; agitation/irritability;
fatigue; tiredness; and ataxia (Eisai Pharma International
Ltd., 2004). Similarly, the Cochrane review of four trials
reported that ataxia, dizziness, somnolence and agitation
were associated with zonisamide therapy (Chadwick and
Marson, 2005). As with other AEs, CNS events are generally
reported early during treatment, and are more common dur-
ing dose titration than at steady-state (Brodie et al., 2005).
Renal calculi
Carbonic anhydrase inhibitors have been linked to an
increased risk for renal calculi, and since zonisamide weakly
inhibits carbonic anhydrase activity in vitro, the potential
for renal calculi to occur during zonisamide therapy war-
rants investigation. However, no renal calculi were reported
in the US and European placebo-controlled trials (Faught et
al., 2001; Sackellares et al., 2004; Brodie et al., 2005), while
a review of 1008 patients in Phase II and III trials in Japan
showed only two patients who developed renal calculi, both
of whom had a family history of nephrolithiasis (Yagi and
Seino, 1992; Lee, 2002).
Renal calculi may be associated with high doses and long-
term treatment (Faught, 2004). In a long-term extension of
an early US trial (median zonisamide dose 500 mg/day), four
cases of symptomatic renal calculi were reported amongst
113 patients receiving up to 96 weeks of continuous treat-
ment (3.5%) (Leppik et al., 1993). However, in an open-label
extension of the early European placebo-controlled trial,
only one patient developed renal calculi (Brodie, 2004).
The overall incidence of renal calculi, calculated from clin-
ical studies and post-marketing surveillance, is reported as
uncommon and occurring in ≤1% of patients receiving zon-
isamide (Eisai Ltd., 2006).
Although renal calculi may occur at a higher rate with
zonisamide treatment than in the general population, care-
ful patient management (e.g. appropriate fluid intake)
reduces the risk. Treatment discontinuation may not be nec-
essary for patients who develop asymptomatic renal calculi.
In a follow-up study, three patients who developed renal cal-
culi all remained asymptomatic with continued zonisamide
therapy (Richards et al., 2005).
Weight change and appetite decrease
Weight loss and appetite decrease (anorexia) are com-
monly encountered as a result of zonisamide treatment. The
Cochrane review of four placebo-controlled trials reported a
80 M. Baulac, I.E. Leppik

Table 2 Summary of adverse events occurring in >5.0% of patients from four placebo-controlled trials [Eisai Ltd., Data on
file(b)]

Adverse events Percentage of patients

All doses of zonisamide (n = 498) Placebo (n = 350)

Total 77.9 67.7

Body as a whole
Abdominal pain 7.2 3.4
Headache 12.4 12.6
Infection 8.0 8.0
Digestive
Appetite decrease (anorexia) 10.8 4.3
Diarrhoea 5.8 3.7
Nausea 9.6 8.0
Nervous system
Agitation/irritability 7.4 4.9
Ataxia 5.6 2.3
Confusion 5.6 2.6
Depression 6.2 2.9
Difficulty concentrating 6.4 2.0
Dizziness 15.5 8.3
Fatigue 6.6 6.3
Insomnia 5.4 3.1
Somnolence 16.1 8.3
Tiredness 8.6 6.9
Special senses
Diplopia 7.0 3.7

significant association of appetite decrease with zonisamide
treatment compared with placebo (99% confidence interval
3.0) (Chadwick and Marson, 2005). However, the major-
ity of patients in placebo-controlled trials lost less than
5 kg (Faught et al., 2001; Sackellares et al., 2004; Brodie
et al., 2005). In one review of clinic experience, mean
weight significantly decreased (p < 0.001) following zon-
isamide treatment (mean duration 11 months), mean weight
before zonisamide was 76.8 kg compared with 73.76 kg after
treatment (Tran et al., 2002). This review also showed that
weight loss was greater for women than for men. These
results contrast with those of several other AEDs, including
two of the most common first-line therapies, carbamazepine
and sodium valproate, which are associated with weight gain
(Biton, 2003). As the effect of weight loss appeared to be
independent of concomitant AEDs (Tran et al., 2002) com-
bination therapy with zonisamide may be helpful to offset
the weight gain associated with these drugs.
Oligohydrosis in paediatric patients
Oligohydrosis and secondary fever have been reported
in children treated with zonisamide but these are rare
(Racoosin and Knudsen, 2004; Glauser and Pellock, 2002). A
recent review of available data in the USA identified 11 cases
of oligohydrosis and/or hyperthermia in patients aged ≤18
years, considered to be related to zonisamide. The report-
ing rate was estimated at 1 case per 4590 patient-years of
exposure, during the first 3 years of zonisamide marketing in
the USA. In all these cases, oligohydrosis was reversible on
discontinuation of zonisamide (Low et al., 2004). Although a
rare event, awareness of the potential of oligohydrosis in the
paediatric population, particularly during the summer and
in warm climates, should help prevent morbidity (Knudsen
et al., 2003).
Rash
Drugs containing sulphonamide moieties are associated
with skin rash but these are most commonly reported
in patients receiving sulphonamide antimicrobials (Tilles,
2001). Although an association between hypersensitivity to
treatment with antibiotic sulphonamide drugs and subse-
quent treatment with a nonantibiotic sulphonamide drugs
has been noted, this is believed to be more related
to a predisposition to allergic reactions rather than to
cross-reactivity (Strom et al., 2003). Zonisamide is a ben-
zisoxazole derivative, which contains a sulphonamide group.
In placebo-controlled trials of adjunctive zonisamide ther-
apy, the incidence of rash as an AE was 3% (Eisai Pharma
International Ltd., 2004), although an additional study indi-
cated that less than half the cases of rash reported in
zonisamide studies could be attributed to the drug (Penovich
et al., 2003). No apparent relationship has been discerned
between zonisamide dose and occurrence of rash (Eisai
Pharma International Ltd., 2004).
Furthermore, post-marketing experience from Japan
has reported low rates of serious skin reactions, such
Efficacy and safety of adjunctive zonisamide therapy
as Stevens—Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN), at 46 per million patient-years of exposure
(Eisai Pharma International Ltd., 2004).
Teratogenicity
Despite the availability of zonsiamide in Japan since 1989,
there is an unfortunate paucity of data to inform the rates of
congenital malformation when administered to women who
are or who become pregnant. However, preclinical studies
demonstrated a teratogenic potential, and consequently, as
for all other AEDs, the use of zonisamide is contra-indicated
in pregnancy. Outcome data from pregnancy registers of
all AEDs generally suggest a two- to three-fold increase in
the risk of malformation compared to no usage, and fur-
ther increased risk when multiple AEDs are administered
(Beghi et al., 2001; Adab et al., 2004; Breen and Davenport,
2006). Pregnancy outcome data specific to zonisamide is
being added to European registers as it accumulates and
will be reported in due course.
Conclusion
Most patients with partial epilepsies that are refractory to
monotherapy are likely to receive adjunctive AED therapy.
However, at present guidelines for the combination of AEDs
remain empirical. When selecting appropriate adjunctive
agents, the theoretical approach to rational polypharmacy
may allow early identification of the most appropriate drug
combination. This should include consideration of the spec-
trum of efficacy, tolerability, modes of action and potential
for interactions between concomitant AEDs.
In this context addition of zonisamide may be worth con-
sideration in that it has multiple mechanisms of action that
are potentially complementary with other AEDs, predictable
pharmacokinetic profile allowing convenient once- or twice-
daily dosing, and no clinically relevant interactions with
the most commonly administered first-line AEDs (e.g. car-
bamazepine).
In placebo-controlled studies in partial seizures, zon-
isamide has demonstrated efficacy at doses of 300—
500 mg/day. Furthermore, a substantial body of supporting
evidence exists from retrospective reviews and open-label
studies. Zonisamide can be titrated to an optimum dosage
according to clinical effect, with some patients benefiting
from treatment at relatively low doses.
In addition to its effects on partial onset seizures, uncon-
trolled data suggest beneficial effects as adjunctive therapy
that extend across a range of seizure types and syndromes,
including generalised epilepsy (Thomas and McCabe, 2005;
Conry et al., 2005), juvenile myoclonic epilepsy (O’Rourke
et al., 2005), progressive myoclonic epilepsy (Welty et al.,
2003; Vossler et al., 2002; Seino et al., 2002; Mullin et al.,
2001; Valeriano and Lane, 2001).
Although side effects are a feature of all AED therapies,
those associated with zonisamide treatment are generally
of mild-to-moderate severity and diminish with continued
treatment. The incidence of AEs during zonisamide therapy
can be reduced by careful patient management, such as slow
dose titration and appropriate hydration.
81
In conclusion, zonisamide is an efficacious AED that is a
potentially useful component in the adjunctive therapy of
partial onset seizures.
Acknowledgements
ACUMED® provided editorial and project management sup-
port for this manuscript. Funding for this support was
provided by Eisai Ltd.
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